1. Field of the Invention
This invention relates to a particle-size reduction apparatus, sterilisation thereof and use thereof to prepare suspensions of drugs, in particular for administration via nebulizers.
2. Description of the Related Art
Previously it was acceptable for drugs intended for use in nebulizers to be prepared under “clean” conditions. Recently, however, such formulations have caused problems in the US due to contamination, and the US FDA has implemented a requirement for all nebulizer solutions to be sterile. In the light of the US FDA decision it is necessary to produce sterile suspension drugs in the US.
The sterilisation of suspensions raises particular problems. The standard means of sterilisation—that is, the raising of the temperature of the formulation to 121° C. for 15 minutes—frequently destroys one or more of the components of the formulation, so only chemically thermostable products can be sterilised by this method. The desired biological activity of the formulation commonly requires that the mass median diameter of particles of the drug lie within a narrow range (average diameter typically less than 5 μm). End sterilisation may alter particle size. In addition this treatment results in the clumping or agglomeration of the drug particles in the suspension such that the efficacy of the resulting product is impaired or abolished.
Known alternative methods for the sterilisation of pharmaceuticals are inappropriate for sterilising suspension formulations of drugs. Solutions of pharmaceuticals may be sterilised by passage though a filter having a pore size of not more than 0.2 μm. However this cannot be used in the case of suspensions as the required particle size in these formulations (typically 2-5 μm) is significantly greater than this filter pore size. Similarly, pharmaceuticals may generally be sterilised by gamma-irradiation, but Budesonide, for example, is destroyed by such treatment (see for example, WO 00/25745). Cold sterilisation using ethylene oxide and carbon dioxide is also known, but stability of Budesonide under these sterilisation conditions has yet to be demonstrated. No further methods for the sterilisation of pharmaceuticals are currently acceptable to regulatory agencies.
Drugs typically provided as nebule suspensions are the steroids Fluticasone and Budesonide, which are used to treat asthma and chronic obstructive pulmonary disorder. These drugs are very insoluble in water and are sold as non-sterile powders.
A method of sterilising dry, powdered Budesonide is known from WO 99/25359. This method of sterilisation is, however, problematic as it requires Budesonide powder to be sterilised and then mixed with the other components of the formulation under sterile conditions. The drug formulation is subsequently prepared under sterile conditions.
International Application No. PCT/GB03/00702 (incorporated herein by reference) describes a solvent based sterilisation method for sterilising pharmaceuticals, in particular suspensions of drugs for use in nebulizers. A sterile composition of a pharmaceutical compound is prepared by combining solvent with a non-sterile pharmaceutical compound to form a solution, and then filtering the solution to yield a sterile pharmaceutical compound. All or part of the solvent is optionally removed to form a suspension, and under sterile conditions the compound is combined with a pharmaceutically acceptable carrier.
In order to be effective in the lungs, the particle size of an active ingredient in a suspension must be within a certain size range—typically the mass median diameter of the particles in the suspension is less than 10 μm. The sterile suspension may, therefore, be passed through a particle-size reduction apparatus, such as a homogenizer, Microfluidizer®) or similar device to reduce the average mass median diameter of the particles.
A suitable device, referred to as a Microfluidizer®), is available from Microfluidics, Inc. (MFIC), described in WO 99/07466 (incorporated herein by reference). Examples of Microfluidizer®) apparatus suitable for production scale particle-size reduction of a pharmaceutical suspension include the M-610 and M-210EH series machines. However, these devices cannot be sterilised.
Particle-size reduction apparatus such as the Microfluidizer®) apparatus typically operate under high pressures and comprise a plunger and a seal to separate the high pressure end of the apparatus from the low pressure end.
It is extremely important that the plunger seal maintains its integrity throughout the particle-size reduction process because if the seal were to fail, the sterility of the process could be compromised. The seal is therefore a high maintenance component that needs to be regularly removed for inspection and/or replaced.
Prior art apparatus is routinely supplied with more than one (most often two) interaction chambers arranged in series; with the first interaction chamber having internal conduits of the smallest size, having a circular cross-section with a diameter in the range from 10 μm, preferably 30 μm to 150 μm, more preferably to 100 μm; and the second interaction chamber having internal conduits of larger size, having a circular cross-section with a diameter in the range from 200 μm, preferably 300 μm to 600 μm, more preferably to 500 μm. For example, the M-120EH machine is supplied with interaction chambers in which the first chamber has conduits with dimensions down to approximately 78 μm and the second chamber with dimensions down to approximately 400 μm.
Our co-pending application (International Application No. PCT/GB04/03574), addresses some of the disadvantages discussed above. In particular, a sterilisable particle-size reduction apparatus is described, along with component parts that help sterilisation to be achieved. This apparatus can, therefore, be used for the production of a sterile suspension of a drug, such as Budesonide, for use in a nebulizer.
However, the apparatus described in PCT/GB04/03574 and other prior art apparatus have the disadvantage that they can become blocked, for example, by particles of the suspended material. Particularly susceptible to becoming blocked are component parts that contain flow passages/conduits having relatively small transverse cross-sectional area, such as an interaction chamber, which is used to reduce the size of particles in a suspension (described in more detail later).
For example, in order to achieve a sufficient degree of comminution and an appropriate size distribution and morphology, the recommended particle-size reduction method using the prior art Microfluidizer®) apparatus employs an interaction chamber having three 87 μm diameter, circular flow passages (i.e. having a transverse cross-sectional area of approximately 5.9×103 μm2).
It is important to minimise the possibility of a particle-size reduction apparatus becoming blocked because blockages can be difficult to detect, especially when using interaction chambers containing more than one flow passage, and blockages can prevent the complete sterilisation of the apparatus.
A further disadvantage of prior art methods that employ relatively small diameter flow passages, e.g. 87 μm diameter, circular flow passages as discussed above; is that such methods optimally require the use of high pressure pumps (generating up to 210 MPa [30,000 psi]), to force suspension around the apparatus. Such high-pressure pumps can be difficult to sterilise.
It is an object of the invention to overcome or at least ameliorate problems associated with the prior art apparatus.
It has now surprisingly been found that an acceptable reduction in particle size, as well as a suitable particle size distribution may be achieved using one or more interaction chambers having flow passages that are substantially larger than was hitherto considered to be necessary.